The present invention relates to a process for producing a hydrogen bromide salt of a (Z)-2-aminothiazole derivative which is useful as an intermediate of pharmaceuticals, for example, an intermediate for constructing a side chain part of the antibiotics disclosed in EP467647B1, which corresponds to Japanese Patent No. 2618119.
A process for producing a hydrogen bromide salt of the (Z)-2-aminothiazole derivative is disclosed in Preparation 6 of EP467647B1, however, the process is not always satisfactory as an industrial production method in that no reproducible particulars on how to control the exothermic reaction is disclosed. Hence an improved process has been desired.
An object of the invention is to provide a method for producing an acid salt of a (Z)-2-aminothiazole derivative of the formula I as depicted below.
Another object of the invention is to provide an industrially advantageous reaction method, particularly a continuous method, for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (I), while effectively controlling the exothermic reaction on an industrial scale production.
The present invention provides:
1. a process for producing an acid salt of a (Z)-2-aminothiazole compound of the formula (I): 
xe2x80x83wherein
R1 and R2 independently represent an alkyl group having 1 to 5 carbon atoms,
Y represents a halogen atom, xe2x80x94OSO3H or xe2x80x94OPO(OH)2,
m indicates the valence number of an inorganic acid of HY and
n indicates an integer of 1 or 2,
which process comprises:
reacting an acid salt of a 2-aminothiazole compound of the formula (II): 
wherein R1 and R2 independently represent an alkyl group having 1 to 5 carbon atoms, the wavy line means that this compound is a mixture of the E- and Z-isomers, and X represents a bromine atom or an iodine atom, with an inorganic acid of the formula (III):
HYxe2x80x83xe2x80x83(III)
wherein Y represents a halogen atom, xe2x80x94OSO3H or xe2x80x94OPO(OH)2;
2. a continuous process for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (IV): 
wherein R1 and R2 independently represent a lower alkyl group having 1 to 5 carbon atoms, and the wavy line means that this compound is a mixture of the E- and Z-isomers,
which process comprises:
continuously feeding thiourea and a 2-alkylidene-4-bromoacetoacetic acid ester of the formula (V): 
wherein R1 and R2 have the same meaning as defined above, and the wavy line means that this compound is a mixture of the E- and Z-isomers, into a reaction vessel having at least one agitator,
reacting the thiourea and the compound of the formula (V) together in the reaction vessel for a sufficient residence time for the conversion of the compound of the formula (V) to the compound of the formula(IV), and
withdrawing a resulting reaction mixture containing the compound of the formula (IV) from the reaction vessel as an effluent; and
3. a process for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (IV) as defined above,
which process comprises:
reacting thiourea and a 2-alkylidene-4-bromoacetoacetic ester of the formula (V) as defined above, wherein the reaction temperature of the reaction is maintained at a temperature of xe2x88x9210 to +45xc2x0 C. and the reaction time Rt of the reaction is defined by the following inequality:
60e(xe2x88x920.15T)xe2x89xa6Rtxe2x89xa6180e(xe2x88x920.1T),
wherein xe2x80x9cTxe2x80x9d means a reaction temperature.
In the present invention the term xe2x80x9cRtxe2x80x9d stands for both xe2x80x9cReaction Timexe2x80x9d (when reference a batch reaction in a reaction vessel), and xe2x80x9cResidence Timexe2x80x9d (when reference continuous reaction in a reaction vessel).
First, a description will be made to the first aspect of the present invention drawn to the process for producing an acid salt of a (Z)-2-aminothiazole compound of the formula (I), which process comprises reacting an acid salt of a 2-aminothiazole compound of the formula (II) with an inorganic acid of the formula (III).
Examples of the lower alkyl group having 1 to 5 carbon atoms for R1 and R2 of the formulae (I), (II) and (VI) each independently include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a n-pentyl group and a neopentyl group.
Examples of the lower alkyl group having 1 to 5 carbon atoms for R1 and R2 of the formulae (IV) and (V) described for the second aspect of the present invention also include the same as described above.
The group Y in the acid salt of the (Z)-2-aminothiazole compound of the formulae (I) and (III) represents a halogen atom such as chlorine, bromine and the like, or represents xe2x80x94OSO3H or xe2x80x94OPO(OH)2.
The X in the acid salt of the 2-aminothiazole compound of the formula (II) represents a bromine atom or an iodine atom.
Examples of the acid salt of the 2-aminothiazole compound of the formula (II) include hydrogen bromide salts or hydrogen iodide salts of the following compounds:
methyl 2-(2-aminothiazole-4-yl)-2-butenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-butenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-butenoate,
methyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
methyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
methyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-octenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-octenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-octenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-octenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-octenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-octenoate and
n-pentyl 2-(2-aminothiazole-4-yl)-2-octenoate,
and mixtures of two or more of these acid salts.
Z-isomer rich hydrogen bromide salts of the above-described 2-aminothiazole derivative are preferably used in the present process and can be obtained by a known method or by the methods of the present invention described below.
Examples of the inorganic acid of the formula (III) include hydrogen halide such as hydrogen chloride and hydrogen bromide, sulfuric acid, phosphoric acid, and the like. Preferred are hydrogen chloride and hydrogen bromide, and hydrogen chloride is used more preferably. Although the inorganic acid is usually used singly, mixtures of two or more inorganic acids can be used. The amount of the inorganic acid to be used is 0.3 to 10 moles, preferably 0.5 to 5 moles per mole of the acid salt of the 2-aminothiazole compound (II).
Although an anhydrous inorganic acid such as a gaseous inorganic acid can be used, an aqueous solution of the inorganic acid is usually used. The concentration of the aqueous acid solution is usually 2 to 99%, preferably 4 to 70%.
Alternatively, a solution of the anhydrous inorganic acid (III) absorbed in an organic solvent also can be employed. Examples of the organic solvent include:
aromatic hydrocarbons such as benzene, toluene and xylene;
aliphatic hydrocarbons such as hexane and heptane;
halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, 1-chlorobutane and chlorobenzene,
ethers such as diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diglyme and triglyme;
ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone;
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone;
alcohols such as methanol, ethanol, 1-propanol, 2-propanol and 1-butanol; and
nitriles such as acetonitrile. Such organic solvents may be used either singly or in mixtures of two or more of them.
The amount of the organic solvent to be used is usually 0.2 to 50 parts, preferably 0.5 to 20 parts per 1 part by weight of the inorganic acid (III).
The reaction between the acid salt of the 2-aminothiazole compound of the formula (II) and the inorganic acid of the formula (III) is usually carried out in the presence of a solvent. Examples of the solvent include those as exemplified above for absorbing gaseous inorganic acid as well as water.
Such solvents are used singly or in combinations of two or more of them. Preferably, a water miscible organic solvent is used.
Examples of such a water miscible organic solvent include:
ethers such as 1,2-dimethoxyethane, diglyme and triglyme;
ketones such as acetone and methyl ethyl ketone;
amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone;
alcohols such as methanol, ethanol and 2-propanol;
nitriles such as acetonitrile.
The amount of the organic solvent or water to be used is usually 0.5 to 100 parts, preferably 1 to 50 parts per 1 part by weight of the acid salt of the 2-aminothiazole compound (II) .
The reaction of the acid salt of the 2-aminothiazole compound (II) with the inorganic acid (III) is carried out, for example, by adding an aqueous solution of the inorganic acid (III) to a solution containing the acid salt of the 2-aminothiazole compound (II). Alternatively, the solution containing the acid salt of the 2-aminothiazole compound (II) may be added to the aqueous solution of the inorganic acid (III).
The reaction is carried out at temperatures not less than the solidifying point of the reaction mixture. The reaction temperature is usually xe2x88x9240 to 40xc2x0 C., preferably xe2x88x9220 to 20xc2x0 C.
The reaction time is not particularly limited, and usually is about 0.5 to 48 hours.
The acid salt of the (Z)-2-aminothiazole compound of the formula (I) obtained may be added as a seed crystal before or during mixing the acid salt of the 2-aminothiazole compound (II) and the inorganic acid (III), if necessary. Such an addition of the seed crystal may result in smooth precipitation of crystals from the reaction mixture.
After completion of the reaction, the acid salt of the (Z)-2-aminothiazole compound of the formula (I) can be isolated as crystals by filtering the precipitates from the reaction mixture.
The crystals of the acid salt of the (Z)-2-aminothiazole compound (I) thus obtained may be washed with a solvent, if necessary. Examples of the solvent that can be used for washing the crystals include those described above for the reaction of the acid salt of the 2-aminothiazole compound (II) with the inorganic acid (III). Such solvents are used singly or in combination of two or more of them.
The amount of the solvent used is usually 0.1 to 20 parts, preferably 0.3 to 10 parts by 1 part by weight of the acid salt (II) of the 2-aminothiazole compound.
The crystals are washed usually at xe2x88x9240 to 40xc2x0 C., preferably xe2x88x9220 to 20xc2x0 C.
Thus obtained crystals of the acid salt of the (Z)-2-aminothiazole compound of the formula (I) can be dried in a conventional manner. Alternatively, crystals containing the organic solvents used in the reaction and/or washing can be used with no problem without being dried.
When a solvent containing water is used as a solvent in the reaction and/or washing, the acid salt of the (Z)-2-aminothiazole compound of the formula (I) obtained may contain crystal water. Even in such a case, the acid salt of the (Z)-2-aminothiazole compound (I) can be produced and used with no problem.
Thus the acid salt of the (Z)-2-aminothiazole compound of the formula (I) can be obtained. Examples of the acid salt of the (Z)-2-aminothiazole compound (I) include: hydrochlorides, hydrobromides, hydriodides, dihydrochlorides, dihydrobromides, dihydriodides, hydrogen sulfates and 1/3-phosphates of the following compounds:
methyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,
methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,
methyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,
methyl (Z)-2-(2-aminothiazole -4-yl)-4-methyl-2-pentenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
methyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,
methyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl-4,4-dimethyl-2-pentenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-pentyl (Z)-2-(2-aminothiazole-4-yl) -4,4-dimethyl-2-pentenoate,
methyl (Z)-2-(2-aminothiazole -4-yl)-2-octenoate,
ethyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,
n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,
isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,
n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,
t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate and
n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate.
When the substituent X in the acid salt of the 2-aminothiazole compound of the formula (II) is not the same as the group Y in the inorganic acid of the formula (III), the acid salt of a (Z)-2-aminothiazole compound of the formula (I) may be obtained as a mixed acid salt of the (Z)-2-aminothiazole compound of the formula (I) as described above.
The acid salt of the (Z)-2-aminothiazole compound of the formula (I) can, for example, be converted to a free (Z)-2-aminothiazole compound by allowing it to react with a base such as sodium hydrogencarbonate, if necessary.
The acid salt of the (Z)-2-aminothiazole compound (I) as described above can be manufactured and used with encountering no problem.
The acid salt of the 2-aminothiazole compound of the formula (II) that is used in the above-described process, can be prepared, for example, by reacting a halogenated compound of the formula (V): 
wherein
R1 and R2 independently represent an alkyl group having 1 to 5 carbon atoms,
X represents a bromine atom or an iodine atom and the wavy line means that this compound is a mixture of the E- and Z-isomers, with thiourea under similar conditions as described below, but manufacturing conditions or methods of the salt are not particularly limited thereto.
Next, a description will be made to the second aspect of the present invention regarding the continuous process for preferentially producing the compound of the formula (IV) from a 2-alkylidene-4-bromoacetoacetic acid ester of the formula (V).
Although the 2-alkylidene-4-bromoacetoacetic ester of the formula (VI) to be used in the second aspect of the present invention can be obtained, for example, according to the method disclosed in the EP 0467647B1, the production method of the compound is not restricted to the disclosed process.
Specific examples of the 2-alkylidene-4-bromoacetoacetic ester of the formula (VI) include:
methyl 2-ethylidene-4-bromoacetoacetate,
ethyl 2-ethylidene-4-bromoacetoacetate,
n-propyl 2-ethylidene-4-bromoacetoacetate,
i-propyl 2-ethylidene-4-bromoacetoacetate,
n-butyl 2-ethylidene-4-bromoacetoacetate,
t-butyl 2-ethylidene-4-bromoacetoacetate,
n-pentyl 2-ethylidene-4-bromoacetoacetate,
methyl 2-propylidene-4-bromoacetoacetate,
ethyl 2-propylidene-4-bromoacetoacetate,
n-propyl 2-propylidene-4-bromoacetoacetate,
i-propyl 2-propylidene-4-bromoacetoacetate,
n-butyl 2-propylidene-4-bromoacetoacetate,
t-butyl 2-propylidene-4-bromoacetoacetate,
n-pentyl 2-propylidene-4-bromoacetoacetate,
methyl 2-butylidene-4-bromoacetoacetate,
ethyl 2-butylidene-4-bromoacetoacetate,
n-propyl 2-butylidene-4-bromoacetoacetate,
i-propyl 2-butylidene-4-bromoacetoacetate,
n-butyl 2-butylidene-4-bromoacetoacetate,
t-butyl 2-butylidene-4-bromoacetoacetate,
n-pentyl 2-butylidene-4-bromoacetoacetate,
methyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
ethyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
n-propyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
i-propyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
n-butyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
t-butyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
n-pentyl 2-(2-methylpropylidene)-4-bromoacetoacetate,
methyl 2-pentylidene-4-bromoacetoacetate,
ethyl 2-pentylidene-4-bromoacetoacetate,
n-propyl 2-pentylidene-4-bromoacetoacetate,
i-propyl 2-pentylidene-4-bromoacetoacetate,
n-butyl 2-pentylidene-4-bromoacetoacetate,
t-butyl 2-pentylidene-4-bromoacetoacetate,
n-pentyl 2-pentylidene-4-bromoacetoacetate,
methyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
ethyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
n-propyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
i-propyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
n-butyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
t-butyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
n-pentyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,
methyl 2-hexylidene-4-bromoacetoacetate,
ethyl 2-hexylidene-4-bromoacetoacetate,
n-propyl 2-hexylidene-4-bromoacetoacetate,
i-propyl 2-hexylidene-4-bromoacetoacetate,
n-butyl 2-hexylidene-4-bromoacetoacetate,
t-butyl 2-hexylidene-4-bromoacetoacetate,
n-pentyl 2-hexylidene-4-bromoacetoacetate, and the like.
The amount of thiourea to be used is usually from 0.5 to 10 moles, preferably from 0.9 to 5 moles per mol of the 2-alkylidene-4-bromoacetoacetic ester of the formula (VI).
In the continuous process of the present invention, the reaction is preferably conducted so that the resulting mixture is preferably maintained at a predetermined temperature (e.g., xe2x88x9210 to +45xc2x0 C.) so that undesirable side reactions are reduced, and the reactor is designed to have sufficient residence time for the conversion of the fed reactants.
The solution of the 2-alkylidene-4-bromoacetoacetic acid ester and a solution of thiourea are usually continuously charged by a pump such as a gear pump, syringe pump and the like into the reaction vessel.
The reaction vessel usually contains a transfer line connected ahead to a tubular reactor which may be further connected with a transfer tubular line. The solutions of the reactants (thiourea and the compound of the formula (V)) are usually continuously fed into the transfer line connected ahead to a tubular reactor or directly into the reactor in which the reactants are thoroughly mixed by an agitator equipped thereto, and further conversion of the reactants is allowed in the following transfer tubular line, if necessary.
Examples of the reaction vessel to be used in the present invention include a tubular reactor having at least one agitator arranged singly or in series which can cause a sufficient turbulent flow to the charged reactant solutions.
Examples of the agitator include:
a static mixer, wherein variously shaped vanes causing a turbulent flow of the reactant solutions are placed in a tubular casing,
an agitator wherein a vane placed in a tubular casing is rotated so as to make a turbulent flow as described above,
an agitator having a vane fixed to the inner wall of a tubular casing and a stirrer fixed to a shaft that is mounted in the tubular casing and reciprocates in the axis direction, and
an agitator having a helical vane fixed to a shaft which is set in the tubular casing and the shaft is connected to a vibration source, wherein the helical vane and the tubular casing form a helical passage for the reactant solution.
Among these, preferably employed are:
a static mixer (e.g., Noritake Static Mixer manufactured by Noritake Company, Limited, TK-ROSS LPD Mixer and Motionless Mixer manufactured by Tokusyukika-kogyou, Ltd, Sulzer Mixer manufacture by Sumitomo Heavy Industries, Ltd, Myu Mixer manufactured by Iken Kogyou, Ltd, Square Mixer manufacture by Sakura Seisakusyo, Ltd, Satake Multiline Mixer manufactured by Satake Kagaku Kikai Kogyou, Ltd and Pipeline Agitator manufacture by Shimazaki Seisakusyo, Ltd.),
an agitator having a helical vane fixed to a shaft which is set in the tubular casing and the shaft is connected to a vibration source or to a crankshaft of a motor, thereby forming a helical passage for the reactant solutions as disclosed in JP 4-235729 A and Journal of Fermentation and Bioengineering Vol. 78, No.4.pp293-297, 1994, the whole disclosures of which are incorporated herein by reference.
The tubular reactor of the present invention may be further partitioned with a plurality of perforated partition plates which are set in the tubular line to mix the reactant solution flow in a plurality of stages.
A mixed reaction solution obtained by feeding and mixing a solution of the 2-alkylidene-4-bromoacetoacetic ester and a solution of thiourea in a tubular reactor may thereafter be passed through an ordinary tubular line, i.e., pipe to be retained for a desired residence time (reaction time).
The reactants of the formula (V) and thiouera are usually fed into the reactor as a solution in a solvent. Examples of the solvent to be used include those organic solvents used in the first aspect of the present invention. The solvents may be used singly or in combination of two or more of them. The amount of the solvent used is not particularly limited and is usually from 0.5 to 100 parts, preferably from 1 to 30 parts per 1 part by weight of the 2-alkylidene-4-bromoacetoacetic ester of the formula (V).
The amount of the solvent to be used for dissolving thiourea is such an amount that does not allow to precipitate the thiourea at a reaction temperature described below. Preferably used are amide solvent as described above to dissolve the thiourea.
The reaction is preferably conducted at a temperature of from xe2x88x9210 to 45xc2x0 C. so that the highest sustainably controlled temperature of the reaction is maintained at a temperature of from xe2x88x9210 to 45xc2x0 C. Even more preferably the reaction is conducted at a temperature of from 0 to 35xc2x0 C. so that the highest sustainably controlled temperature is maintained at a temperature of from 0 to 35xc2x0 C.
The resulting reaction mixture is usually withdrawn from the reaction vessel as an effluent, which is, for example, then immediately cooled to reduce undesirable side reactions, such as the isomerization reaction of the desired hydrogen bromide salt of the (Z)-2-aminothiazole derivative to its E-isomer. The reaction mixture is for example, cooled usually to 0xc2x0 C. or less, preferably to xe2x88x9210xc2x0 C. or less, and more preferably to xe2x88x9230xc2x0 C. or less to effectively suppress isomerization reaction. Alternatively, the withdrawn reaction mixture may be added dropwise to an aqueous acidic solution as used in the first aspect of the present invention.
Therefore, residence time (reaction time) Rt is preferably set at a range defined by the following inequality:
xe2x80x8360e(xe2x88x920.15T)xe2x89xa6Rt xe2x89xa6180e(xe2x88x920.1T),
wherein xe2x80x9cTxe2x80x9d is the highest sustainably controlled temperature.
The method of cooling may be, but is not restricted to, being carried out by cooling the reaction mixture obtained indirectly using a refrigerant, or by directly pouring the reaction mixture into a solvent previously cooled such as 1-chlrobutane and the like, or by adding a cooled material such as a solvent previously cooled and/or dry ice to the effluent reaction mixture, and the like.
Alternatively, the reaction can be carried out by mixing a solution of the 2-alkylidene-4-bromoacetoacetic ester of the formula (IV) and a solution of thiourea quickly under similar reaction conditions as described above taking account of the exothermic amount of the reaction but in a single stage reaction within the above-described preferable reaction temperature and time.
The process of the present invention can preferentially produce the Z-isomer of the hydrogen bromide salt of the 2-aminothiazole derivative, which is useful as an intermediate to pharmaceuticals and can be further purified advantageously as a desired Z-isomer by the present method as described above.